1. Technical Field
The embodiments herein generally relate to the field of tissue engineering and particularly to tissue regeneration, reconstruction, repair, augmentation and replacement. The embodiments herein more particularly relate to a method for regeneration, reconstruction, repair, augmentation and replacement of organs or tissue structures. The embodiments herein also relate to bio-absorbable and biocompatible injectable matrixes for regeneration, reconstruction, repair, augmentation or replacement of organs or tissue structures shaped to conform to at least a part of organs or tissues. Moreover, the embodiments herein also relate to materials for bio-absorbable and biocompatible injectable matrixes.
2. Description of the Related Art
Tissue engineering has emerged as a multi-disciplinary field which combines biology, materials science and surgical reconstruction. Tissue engineering provides living tissue products which can be restored and maintained in order to provide improved tissue function. The need for this approach has arisen primarily due to the lack of donor organs and tissues. Tissue engineering offers a promise of being able to dramatically expand the ability to repair tissues and develop improved surgical procedures. In general, there are three distinct approaches which are currently being used to engineer new tissues. They are: firstly, infusion of isolated cells or cell substitutes, secondly, use of tissue inducing materials and/or tissue regeneration scaffolds (sometimes referred to as guided tissue repair) and thirdly, implantation of cells seeded in scaffolds (either prior to or subsequent to implantation). In the third case, the scaffolds may be configured either in a closed manner to protect the implanted cells from the body's immune system or in an open manner so that the new cells can be incorporated into the body.
In open scaffold systems and guided tissue repairs, tissue engineering devices have normally been fabricated from natural protein polymers such as collagen, chitosan or from the synthetic polymers such as the FDA approved materials including polyglycolic acid (PGA), polylactic acid (PLA), polyglactin 910 (comprising a 9:1 ratio of glycolide per lactide unit known as VICRYL™), polyglyconate (comprising a 9:1 ratio of glycolide per trimethylene carbonate unit known as MAXON™) and polydioxanone (PDS). The natural protein polymers and the synthetic polymers degrade over time in both the cases and are replaced by new tissue. While some of these materials have proved to be good substrates for cell and tissue growth and provide good scaffolding to guide and organize the regeneration of certain tissues. But still they often do not have the specific mechanical requirements that a scaffold should have until a new tissue is developed and is able to take over its functions. Also, these materials are sometimes difficult to process and fabricate into the desired form or are handled poorly in the operating room. At times, they are difficult to suture and fall apart prematurely. For example, it has been reported that tissue engineered heart valve leaflet scaffolds derived from polyglactin and PGA are too stiff and had caused severe pulmonary stenosis when implanted in sheep (Shinoka, et al., “New frontiers in tissue engineering: tissue engineered heart valves” in Synthetic Bioabsorbable Polymer Scaffolds (Atala & Mooney, eds.) pp. 187-98 (Birkhäuser, Boston, 1997)).
Attempts have been made to develop new bio-absorbable and biocompatible polymers with more flexible and elastomeric properties. Among them one approach is to incorporate lactide or glycolide and caprolactone joined by a lysine-based di-isocyante into a polyurethane (Lamba, et al., “Degradation of polyurethanes” in Polyurethanes in Biomedical Applications, pp. 199-200 (CRC Press LLC, Boca Raton, Fla., 1998). However, these cross-linked polyurethane networks cannot be processed by standard techniques such as solution casting or melt processing thus limiting their usefulness. Also, there is no evidence that these polyurethane segments are completely biodegraded in vivo. A commercial material, known as TONE™ has also been evaluated as an elastomeric implant material. But, this material degrades very slowly in vivo and thus has a limited application (Perrin, et al., “Polycaprolactone” in Handbook of Bioabsorbable Polymers (Domb, et al., eds.) pp. 63-76 (Harwood, Amsterdam, 1997)). Another approach to synthesize protein-based polymers particularly the polymers containing elastomeric polypeptide sequences has been there (Wong, et al., “Synthesis and properties of bioabsorbable polymers used as synthetic matrices for tissue engineering” in Synthetic Bioabsorbable Polymer Scaffolds (Atala & Mooney, eds.) pp. 51-82 (Birkhäuser, Boston, 1997). But is not reported to biodegrade in vivo although the cells can invade matrices derived from these materials. They also lack the advantages of thermoplastic polymers in fabrication of devices.
U.S. Pat. Nos. 5,468,253 and 5,713,920 both to Bezwada et al., disclose bio-absorbable elastomeric materials which are used to form devices and are alleged to get completely bio-absorbed within a year or six months according to the in vitro data. However, deGroot et al., Biomaterials, 18:613-22 (1997) provides in vivo data for these materials and reports that the implanted material fragmented after 56 weeks into white crystalline-like fragments. It is suspected that these fragments are crystalline poly-L-lactide which degrades slowly. Nonetheless, whatever the composition of the fragments be the material is not completely bio-absorbed even after one year in vivo. These materials are also difficult to process and may have poor shelf stability.
Tissue engineering for regenerative medicine purposes involves the reconstruction of tissue equivalents to replace the physiologic functions of tissues lost due to disease or injury. Tissue engineering requires the use of a cell source to allow for the generation and maintenance of tissue-specific biological functions as well as the use of synthetic or natural injectable matrix materials to support and guide tissue development. Engineering a complex organ such as lung, liver, kidney, heart or small intestine presents so many scientific challenges that development of clinically applicable replacement tissues has not yet been realized. Problems to be faced in the development of any complex tissue, including lung, depend on the following: the development of better systems to promote angiogenesis, the selection of appropriate cell sources, the reproducible differentiation of the selected cell type or types along organ-specific lineages and the development of appropriate scaffolds or matrices to enhance and support three-dimensional (3D) production of tissues. Because complex organs such as the lung involve more than one cell type, an understanding of the factors involved in the differentiation potential of the selected cell source is invaluable. A major problem in engineering of any tissues for clinical application is selecting human cell sources with the potential to provide sufficient number of cells for development of tissue used to repair critical defects caused by disease or injury beyond the repair capabilities of the human body.
A preferred fabricated form of the composition is a porous (fibrous) construct particularly the ones which can be used as tissue engineering scaffolds and guided tissue repair meshes and matrices. This construct or matrix can be derived by any suitable method including salt leaching, sublimation, solvent evaporation, spray drying, foaming and processing of the materials into fibers and subsequent processing into woven or non-woven devices. Such constructs can be used in tissue engineering applications for the tissues of the cardiovascular, gastrointestinal, kidney, genitourinary, musculoskeletal and nervous system as well as for those of the oral, dental, periodontal and skin tissues. Examples of such constructs can be used to prepare tissue engineering scaffolds for both hard and soft tissues. Representative tissue types include, but are not limited to, cardiovascular (including blood vessel, artery and heart valve), cornea and other ocular tissues, pancreas, alimentary tract (e.g. esophagus and intestine), ureter, bladder, skin, cartilage, dental, gingival tissue, bone, liver, kidney, genital organs (including penis, urethra, vagina, uterus, clitoris and testis), nerve, spinal cord, meniscus, pericardium, muscle (e.g. skeletal), tendon, ligament, trachea, phalanges and small joints, fetal and breast.
In general, there is a worldwide shortage of healthy organs for transplant particularly the epithelial-derived organs such as the liver, pancreas, thyroid and pituitary. For example, a shortage of livers exists for orthotopic organ transplant, as a source of primary hepatocytes for clinical therapies to treat acute and chronic liver failure and for extracorporeal liver assist devices. Attempts to propagate primary human hepatocytes in culture have met with limited success because adult human hepatocytes, unlike newborn-derived hepatocytes, do not have a high proliferative capacity. Another strategy is to use primary porcine hepatocytes or organs for transplants.
Bioresorbable scaffolds are the materials that can be broken down by the body and do not require mechanical removal. Bioresorbable scaffolds may be used as a temporary scaffolding for transplanted cells and thereby allow the cells to secrete extracellular matrix of their own to enable, in the long term, a complete and natural tissue replacement. The macromolecular structure of these scaffolds is selected so that they are completely degradable and are eliminated after they have achieved their function of providing the initial artificial support for the newly transplanted cells. To be useful in cell transplantations, these scaffolds must be highly porous with large surface/volume ratios to accommodate a large number of cells. The scaffolds must be biocompatible, non-toxic to the cells that they carry and to the host tissue into which they are transplanted. The scaffolds must be capable of promoting cellular interactions, promoting the cells to secrete their own extracellular matrix (ECM) components and allowing the retention of the differentiated function of attached cells.
Polysaccharide matrices, such as for example, alginate scaffolds, have been found to be superior to other scaffolds known in the art such as collagen scaffolds in promoting polarized cell-cell and cell-matrix interactions in cultured hepatocytes. They provide adequate sites for the attachment and growth of a sufficient cell mass to survive and function both in vitro and in vivo; support thick layers of cells, such as cell aggregates; and are capable of maintaining the cells in an active functional state before and after implantation/transplantation into a host tissue, at that time the polysaccharide injectable matrix will also become amenable to vascularization from the surrounding tissue. Polysaccharide matrices do not suffer from the drawback of limiting the survival and growth of the cells adjacent to the injectable matrix surface as the cells increase in number within the injectable matrix. Another advantage of polysaccharide matrices is that they are biodegradable but degrade only slowly in vivo and thereby permit the cells carried thereby to be established and to form their own tissue matrix at the site of transplant up to the point where they no longer require the polysaccharide injectable matrix.
Among the various materials used as medical materials, animal collagen has excellent bio-affinity and histo-compatibility. It has low antigenicity and has the action of promoting host cell differentiation and growth. It has a hemostatic action and is completely degraded and absorbed in the body. Consequently, it has properties that are particularly suitable for use as a medical material. At present, animal collagen types I to XIX have been discovered. Collagen type I to V have been used in a variety of ways as medical materials. In particular, type I collagen, useful as an extracellular injectable matrix is most commonly used. These collagens are extracted and purified from the connective tissue of various organs such as skin, bone, cartilage, tendon and viscus of animals such as cows, pigs, birds, kangaroos and so forth by acidic solubilization, alkaline solubilization, neutral solubilization and enzymatic solubilization. In addition, these extracted collagens may be used as thread for medical treatment.
Further, after a cross-linking treatment using a cross-linking agent or to physical cross-linking treatment using radiation, electron beam, ultraviolet rays on the collagen materials, there was hardly any increase in the physical properties of the collagen material, particularly the tear strength. It was not possible to process this material for use as a medical material requiring suturing. Moreover, when a cross-linking agent such as glutaraldehyde or epoxy was used, the toxicity of the cross-linking agent on the body became a problem. Also, there is a disadvantage with the collagen in the biochemical properties, i.e., after using the collagen material the promotional effects on cell growth is lost. In addition, in the case of physical cross-linking treatment, the cross-linking rate is unstable and providing adequate physical properties to the collagen material is also not possible. Also, it has been difficult to perform a cross-linking treatment in order to control the absorption rate of the collagen in the body.
For these reasons, a need has arisen for the development of a collagen material that possesses physical properties that allow suturing still maintaining the biochemical properties inherently possessed by collagen, retain the shape for a certain amount of time even after application to the body. The process of production of the medical material for the desired organ, for examples, an artificial tube for nerve, an artificial tube for spinal cord, an artificial esophagus, an artificial trachea, an artificial blood vessel, an artificial valve or alternative medical membranes such as artificial endo-cranium, artificial ligament, artificial tendons, surgical sutures, surgical prostheses, surgical reinforcement, wound protecting materials, artificial skin and artificial cornea. In particular, there has arisen a strong need in the clinical setting for the development of various types of medical materials that can be used as alternative medical membranes which present no ethical problems, are in stable supply, prevent adhesion of the surgical wound following surgery after being applied to the body, have no risk of infection, do not cause tissue degeneration, allow control of the rate of degradation following application, and have an action that promotes regeneration of biomembranes, especially endocranium, pericardium, pleura, peritoneum or serous membrane.
Regenerative medicine offers new tools to tackle the difficulty for the disorders for which there is currently no good therapeutic option. The trachea is an ideal organ to explore the clinical potential of tissue engineering because severe large airway diseases have been poorly managed by conventional treatments. The success of a graft is determined only by its ability to conduct air lifelong and become a sustainable biological conduit.
In recent years, accidental trauma, accompanying the progress made in anesthesia control and post-operative control, including operative procedure for malignant tumors of organs in the cervical and thoracic parts, there has been an increase in the number of occasions in which it is necessary to reconstitute the trachea or tracheal bifurcation. Although the most clinically reliable reconstruction methods are direct anastomoses such as end-to-end anastomosis and end-to-side anastomosis. These methods are subject to their own restrictions on the range of reconstruction and even within the allowed range. High-degree anastomotic techniques and relaxation sutures etc. are required. Consequently, these procedures tend to be associated with extensive invasion. At that time, the use of a trachea substitute made of an artificial material (hereinafter to be referred to as an “bioartificial trachea”) enables reconstruction to be performed easily. As a result, the indications for this operation can naturally be expected to be expanded. Attempts in applying such a bioartificial trachea began with animal experiments conducted by Daniel, R A Jr. (published in J. Thorac. Surg. 17, 335 (1948) “The Regeneration of Defects of the Trachea and Bronchi”) and although various attempts have been made using various materials since that time but still no artificial materials that can be sued safely in the clinical application have been developed with the exception of partial prosthesis of the cervical trachea.
In case of bioartificial trachea meant for the intra-thoracic trachea there is the greatest desire for clinical effectiveness, since the bioartificial trachea is subjected to poor conditions like little support and external force. In addition to these common problems, bioartificial trachea requires adequate support, rapid and reliable incorporation in the body with little inflammatory reaction. The countermeasure against leakage of air constitutes the most serious problem.
It is still a great challenge for the surgeons all over the world to reconstruct long-segment defect of the trachea. The best way to resolve this dilemma is tracheal transplantation and artificial prosthesis. However, all the efforts are in vain. Lack of blood supply and rejection hindered transplantation, compatibility with recipients' tissues and not covering with endothelium made all artificial prosthesis only a “stent”.
Bioartificial tracheal prosthesis up to now is a big challenge to entire surgical field all over the world. All kinds of prosthesis used previously are like “inner stent” which cannot be integrated with native trachea. Actually, there is an interface between smooth surface of the prosthesis and living tissue, the inner side of which is not covered with living membrane. Therefore, there is always a chance of infection around the prosthesis.
Tissue engineering for regenerative medicine purposes is the reconstruction of tissue equivalents to replace the physiologic functions of tissues lost due to disease or injury. Tissue engineering requires the use of a cell source to allow for the generation and maintenance of tissue-specific biological functions as well as the use of synthetic or natural injectable matrix materials to support and guide tissue development. Engineering a complex organ such as lung, liver, kidney, heart or small intestine presents so many scientific challenges. The development of clinically applicable replacement tissues has not yet been realized.
Problems to be faced in the development of any complex tissue, including lung, depend on: development of better systems to promote angiogenesis, selection of appropriate cell sources, reproducible differentiation of the selected cell type or types along organ-specific lineages and development of appropriate scaffolds or matrices to enhance and support three-dimensional (3D) production of tissues. Because complex organs such as the lung involve more than one cell type, an understanding of the factors involved in the differentiation potential of the selected cell source is invaluable. A major problem in engineering of any tissues for clinical application is selecting human cell sources with the potential to provide sufficient numbers of cells for development of tissue used to repair critical defects caused by disease or injury beyond the repair capabilities of the human body.
Tracheal defects may occur after trauma or prolonged intubation. Resection of tracheal tumors also poses a major challenge for substitution. In an effort to solve this problem, different techniques have been tried but with little success. The various tracheal substitutes and techniques of reconstruction were analyzed by Grillo, who classified them in five categories: foreign materials, nonviable tissues, autogenous tissues, tissue engineering and tracheal transplantation. But attempts with foreign materials have led to certain problems such as chronic infection, airway obstruction and migration of the prosthesis, erosion of major blood vessels and proliferation of granulation tissue. Also, implantation of nonviable tissues either chemically treated, frozen or lyophilized have been associated with poor functional results. Complex procedures involving reconstruction with autogenous tissues such as skin, fascia lata, pericardium, costal cartilage, bladder, esophagus or bowel have been associated with disappointing results. More recently, efforts have been made to induce the formation of cartilaginous tubes covered with epithelial cells, but to date this type of tissue engineering has not provided reliable results. Moreover, tracheal allo-transplantation has also been disappointing due to complication of necrosis or stenosis of the graft. In addition immunosuppressive therapy does not permit a clinical application in the treatment of cancer. Recently, Martinod and colleges have used autogenic aortic graft and allogenic aortic grafts to replace long segments of tracheal defect and carina using sheep as animal model with promising results. Seguin and colleges have used cryopreserved, decellularized aortic allograft supported by temporary stent to prevent airway collapse.
Thus, while the current bio-absorbable and bio-compatible polymers offer a wide range of useful properties for certain medical applications. It is desirable to develop methods to prepare bio-absorbable and biocompatible polymers that significantly extend the range of properties available. It would thus be desirable to develop methods for preparing bioabsorbable and biocompatible polymers with mechanical properties closer to those of tissue, particularly for soft tissues. It would also be desirable to develop methods for making bioabsorbable biocompatible materials which can be readily processed and fabricated into tissue engineering devices that can be easily implanted. The embodiments herein define the component parts of tissue engineering and review the experimental methods used to produce airway implants to date, including a recent successful, first-in-man experience.
The above mentioned shortcomings, disadvantages and problems are addressed herein and which will be understood by reading and studying the following specification.